Infection in Immunocompromised Patients

Antimicrobial choice in febrile neutropenia

• Aminoglycosides should not be used in the following 3 different group of patients. In these 3 groups of patients, empirical treatment is Ciprofloxacin 10mg/kg (max 400mg) twice a day with Piperacillin / tazobactam – if endoprosthesis in situ, add teicoplanin 
  • Bone tumor patients
  • Patients with established or potential renal impairment
  • Those with a single kidney (e.g. Wilms post nephrectomy)
• If meningitis is suspected, use meropenem (meningeal doses) as piperacillin / tazobactam is not appropriate and seek specialist advice from microbiology/infectious diseases teams.
• Continue cotrimoxazole prophylaxis during febrile neutropenic episode
• Suspect shunt infection in patients presenting with fever and a VP shunt in situ. These patients must be discussed immediately with the neurosurgical team.
• Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria. These include methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), extended-spectrum b-lactamase (ESBL)–producing gram-negative bacteria, and carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC). Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity.
  • MRSA: Consider early addition of vancomycin or linezolid.
  • VRE: Consider early addition of linezolid or daptomycin.
  • ESBLs: Consider early use of a carbapenem.
  • KPCs: Consider early use of polymyxin-colistin or tigecycline.
• Unexplained persistent fever in a stable patient rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly.
• Indications for Addition of Antibiotics in cases of Gram-Positive Organisms in addition to the Empirical Regimen for Fever and Neutropenia:
  1. Hemodynamic instability or other evidence of severe sepsis.
  2. Pneumonia documented radio-graphically.
  3. Positive blood culture for gram-positive bacteria, before final identification and susceptibility testing is available.
  4. Clinically suspected serious catheter-related infection (e.g., chills or rigors with infusion through catheter and cellulitis around the catheter entry/exit site).
  5. Skin or soft-tissue infection at any site.
  6. Colonization with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, or penicillin-resistant Streptococcus pneumoniae.
  7. Severe mucositis, if fluoroquinolone prophylaxis has been given and ceftazidime is employed as empirical therapy.

• Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms.
• Gram-negative bloodstream infections in patients with neutropenia may initially be treated with combinations of b-lactam or carbapenem agents plus aminoglycosides or fluoroquinolones to provide broad initial coverage of possible multidrug-resistant pathogens at the outset of treatment. Once the patient is stable and in vitro susceptibilities are known, antibiotic treatment can be reduced to monotherapy with a b-lactam agent, as it is adequate for most simple bacteraemia during neutropenia.
• Pneumonia in neutropenic patients should generally be treated as a health care–acquired infection according to recent guidelines from the American Thoracic Society. Immunosuppressed patients and those who have been hospitalized or received antibiotics within the previous 90 days are considered to be among those at high risk for developing pneumonia with multidrug-resistant pathogens. An initial broad-spectrum antibiotic with combinations of a b-lactam or carbapenem plus an aminoglycoside or antipseudomonal fluoroquinolone is recommended for these patients.
• In severe cases of pneumonia, as documented by hypoxia or extensive infiltrates, or if MRSA is suspected, vancomycin or linezolid should be added.
• Persistent and unresolving pneumonia should be evaluated with broncho-alveolar lavage and biopsy. Adjustment of the empirical regimen can be guided by the type and sensitivity of pathogens and by clinical progress.
• For patients with gram-positive bloodstream isolates or with skin and soft-tissue infections, the early addition of vancomycin (or linezolid or daptomycin) to the treatment regimen is recommended until sensitivity results are available for the organism(s) that have been isolated.
• Oral ulcerations or symptoms of esophagitis may represent HSV or Candida esophagitis infections in high-risk patients, so empirical addition of acyclovir and/or fluconazole or another antifungal is recommended.
• The onset of severe abdominal pain, typically in the right lower quadrant, suggests neutropenic enterocolitis (also referred to as ‘‘typhlitis’’). A CT should be obtained for additional evaluation. Patients who develop neutropenic enterocolitis should be treated with an expanded broad-spectrum regimen, although the most efficacious regimen is unknown. Because anaerobes and gram-negative organisms can cause neutropenic enterocolitis, monotherapy with piperacillin-tazobactam or a carbapenem or a combination of an anti-pseudomonal cephalosporin plus metronidazole are appropriate antibiotic regimens. There is less evidence to support the routine addition of vancomycin or an antifungal agent to antimicrobial regimens. These patients should be evaluated by a surgeon as bowel resection may be required for uncontrolled sepsis, bleeding, or bowel ischemia.

Antifungals

• In case of neutropenic Invasive fungal disease (IFD) in patients with high risk, initiate empiric antifungal treatment for persistent or recurrent fever of unclear etiology that is unresponsive for ≥ 96 hours to broad-spectrum antibacterial agents.
• Low-risk patients with neutropenic IFD, consider empiric antifungal therapy in the setting of persistent fever and neutropenia.
• Use Micafungin 100 mg daily or caspofungin loading dose 70 mg, then 50 mg daily for empiric antifungal therapy.
• If not available or not tolerated use liposomal amphotericin B (L-AmB) 3–5 mg/kg daily.
• Those who remain febrile after 4–7 days of broad-spectrum antibiotics but are clinically stable, have no clinical or chest and sinus computed tomography (CT) signs of fungal infection, have negative serologic assay results for evidence of invasive fungal infection, and have no recovery of fungi (such as Candida or Aspergillus species) from any site may have antifungal agents withheld.
• Patients at high risk for IFD are those with acute myeloid leukemia, relapsed acute leukemia, those receiving highly myelosuppressive chemotherapy for other malignancies, and allogeneic HSCT recipients with persistent fever (≥ 96 hours) despite prolonged broad-spectrum antibiotic therapy and expected prolonged neutropenia (> 10 days).
• All others should be categorized as being at low risk for IFD.
• Consider prospective monitoring of serum galactomannan (GM) twice per week in IFD high-risk hospitalized patients for early diagnosis of invasive aspergillosis.
• In IFD low-risk patients, do not implement routine GM screening.
• Consider GM in BAL and cerebrospinal fluid to support the diagnosis of pulmonary or CNS aspergillosis.
• In IFD high-risk patients with persistent fever and neutropenia beyond 96 hours, perform evaluation for IFD. Evaluation should include computed tomography (CT) of the lungs and targeted imaging of other clinically suspected areas of infection. Consider CT of the sinuses in patients ≥2 years.

Treatment of documented candidemia

• Start caspofungin: loading dose 70 mg, then 50 mg daily; or micafungin: 100 mg daily; or anidulafungin: loading dose 200 mg, then 100 mg daily) as an initial therapy.
• Lipid formulation AmB, 3–5 mg/kg daily, is an effective but less attractive alternative because of the potential toxicity.
• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, is an alternative for patients who are not critically ill and have no prior azole exposure.
• Fluconazole, 400 mg (6 mg/kg) daily, can be used for step-down therapy during persistent neutropenia in clinically stable patients who have susceptible isolates and documented bloodstream clearance.
• For infections due to C. krusei, start caspofungin, lipid formulation AmB, or voriconazole.
• Continue treatment for 2 weeks after documented clearance of Candida from the bloodstream, provided neutropenia and symptoms attributable to candidemia have resolved.

Treatment of Aspergillosis

• Start voriconazole (6 mg/kg IV every 12 h for 1 d, followed by 4 mg/kg IV every 12 h).
• Amphotericin B (AmB) 3–5 mg/kg daily is an appropriate option for initial and salvage therapy of Aspergillus infections when voriconazole cannot be administered.
• Continue treatment for a minimum of 6–12 weeks, depending on the degree and duration of immunosuppression, site of disease, and evidence of disease improvement.

Antivirals

• Herpes simplex virus (HSV)–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis.
• Antiviral treatment for HSV or Varicella-Zoster virus (VSV) infection is only indicated if there is clinical or laboratory evidence of active viral disease.
• Respiratory virus testing (including testing for influenza, parainfluenza, adenovirus, respiratory syncytial virus (RSV), and human metapneumovirus) and chest radiography are indicated for patients with upper respiratory symptoms (e.g., coryza) and/or cough.
• Yearly influenza vaccination with inactivated vaccine is recommended for all patients under active treatment. Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (7 days after the last treatment) or 2 weeks before the start of chemotherapy.
• Influenza virus infection should be treated with neuraminidase inhibitors if the infecting strain is susceptible (A-II). In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive treatment empirically.
• Routine treatment of RSV infection in neutropenic patients with upper respiratory disease should not be given.

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